The present invention, in some embodiments thereof, relates to chemical synthesis and, more particularly, but not exclusively, to a novel process of preparing Grignard reagents and to uses thereof in organic syntheses.
Metal-organic compounds are widely used in the industry to produce fine chemicals as well as pharmaceutical agents with complex molecule structures. The most common type of such metal-organic compounds is the Grignard reagent (herein also referred to interchangeably as GR), which is formed by the reaction of an organic halide with Magnesium or a similar metal.
Grignard reagent is used in numerous industrial processes involving reactions with C—C bond formation. Examples of industrial processes which utilize Grignard reagent include the synthesis of tramadol [Kleemann et al. Pharmaceutical Substances; Thieme-Verlag: Stuttgart (Germany), 2000; pp. 2085.]; syntheses of various organo-tin compounds [Stoermer, M. J.; Pinhey, J. T. Molecules 1998, 3, M67] used as stabilizers for vinyl chloride resins, catalysts for hardening urethane and other industrial purposes; production of organo-silicon products [Narain, R. P. Mechanisms in organic chemistry; New age international: New Delhi, 2008]; production of organo-phosphorous compounds used for vitamin synthesis [Kolodiazhnyi, O. I. Phosphorous Ylides, chemistry and application in organic synthesis; Wiley-VCH: New-York, 1999] and production of organo-boron compounds used for conjugated polymer synthesis [Tanaka, K.; Chujo, Y. Macromolecular Rapid Communications 2012, 15, 1235-1255]; production of tamoxifen derivatives used in the pharmaceutical industry of flavor enhancers for the food industry in the form of maltol or ethyl maltol, of various anti-inflammatory analgesics such as Naproxen, of pharmaceuticals for pain treatment such as propoxyphene [Richey, H. Grignard reagents—new developments; John Wiley and sons, LTD: New York, 2000] and many other uses.
Grignard reagents form via the reaction of an alkyl or aryl halide with magnesium metal. The reaction proceeds through single electron transfer, as depicted in Scheme 1 below:R—X+Mg→R—X.−+Mg.30 R—X.−→R.+X−R.+Mg.+→RMg+RMg++X−→RMgX  Scheme 1wherein R is alkyl, cycloalkyl or aryl and X is halide.
Alkyl and aryl bromides and iodides are common substrates for preparing Grignard reagent. Chlorides are also used, and fluorides are generally unreactive, except with specially activated magnesium. The reactions involved in preparing a Grignard reagent are typically highly exothermic.
The solvent media plays a key role in formation of Grignard reagent and its following reactions. The most suitable and universally used solvents are ethers, specifically tetrahydrofuran (THF) or diethyl ether.
In practice, the production of Grignard reagent is often difficult, as the surface of the magnesium is usually covered by a layer of hydroxides and oxides such as MgO, which impairs the reaction of the Mg-metal with organic halides. In particular, when Mg is in contact with different organic media, a non-conductive passivation layer is present and slows down or completely prevents chemical and electrochemical reactions that would otherwise occur in its absence [Lu et al. J Electroanal Chem 1999, 2, 203-217; Meitav, A.; Peled, E. J. Electrochem. Soc. 1981, 4, 825-831].
Different initiating methods have been introduced to the synthesis procedure in order to weaken the passivating layer of MgO, and thereby exposing highly reactive magnesium to the organic halide. Mechanical methods include crushing of the Mg pieces in situ, rapid stirring, and sonication of the suspension. Chemical methods involve activating agents such as iodine, methyl iodide, and 1,2-dibromoethane. Physical methods include application of heat and environmental dryness.
Grignard reagents are produced in industry for use in situ, or for sale. As with at bench-scale, the main problem is that of initiation; a portion of a previous batch of Grignard reagent is often used as the initiator.
Grignard reactions are exothermic, and this exothermicity must be considered when a reaction is scaled-up from laboratory to production plant.
Grignard reagents such as methylmagnesium bromide, methylmagnesium chloride, phenylmagnesium bromide, and allylmagnesium bromide are available commercially as tetrahydrofuran or diethyl ether solutions.
Efforts to synthesize GR electrochemically in ethers have been characterized as hazardous and resulted in low yields per unit time [Richey, H. (2000) supra].
Other efforts, which attempt regular chemical GR synthesis in a separate step, suffer from numerous problems such as reduced safety, non-controllability and sluggish reaction rates. In addition, carrying out GR synthesis in a separate step rather than integrating it into a single process combined with subsequent reaction steps, leads to higher costs.
Room temperature ionic liquids, abbreviated RTILs, are a relatively new class of solvents that have been studies thoroughly for the past two decades as an electrolyte media. RTILs are liquids at room temperature that are composed essentially of 100% ions excluding contaminations. Typically, in RTIL, the cations are organic and anions are inorganic.
RTILs are characterized by a wide electrochemical window, low volatility and vapor pressure, high conductivity, chemical stability, low boiling temperature, environmental friendliness and having the ability to adjust different properties by minutely adding or subtracting functional groups on the cation.
Because of these properties, RTILs have found many applications in diverse areas such as bioscience, CO2 capture, organic synthesis and energy management. In particular, a large number of uses have been found in electrochemistry for applications such as electrodeposition, batteries, fuel cells, solar cells, and capacitors.
In the area of Mg electrochemistry, certain non-acidic ionic liquids such as [1-butyl-1-methyl pyrolidinium bis(trifluoromethylsulfonyl)imide] (BMPTFSI) and [N,N-diethyl-N-methyl-N-(2-methoxyethyl) ammonium-bis(trifluoromethylsulfonyl) imide] (DEMETFSI) have been found to be suitable as co-solvents for externally added GRs such as phenyl-magnesium bromide (PhMgBr) and ethyl-magnesium bromide (EtMgBr) [Lu et al., 1999, supra; and Yoshimoto et al. Power Sources 2010, 7, 2096-2098].
Additional background art includes Handy S. T., J. Org. Chem., 2006, 71 (12), pp. 4659-4662, which teaches non-electrochemical Grignard reactions utilizing RTIL as a solvent; and Law et al., Chem. Commun., 2006, pp. 2457-2459.